US7179495B1 - Hyperforin as cytostatic agent and hyperforin ointment or cream as application form - Google Patents
Hyperforin as cytostatic agent and hyperforin ointment or cream as application form Download PDFInfo
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- US7179495B1 US7179495B1 US09/856,694 US85669499A US7179495B1 US 7179495 B1 US7179495 B1 US 7179495B1 US 85669499 A US85669499 A US 85669499A US 7179495 B1 US7179495 B1 US 7179495B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
Definitions
- the present invention relates to the use of hyperforin as a cytostatic agent and to a hyperforin ointment or cream which is suitable as a form for applying the hyperforin.
- Hyperforin and the hypericins are characteristic constituents of St. John's wort (Hypericum perforatum L.), which also contains constituents which occur generally in the plant kingdom, such as flavone derivatives, flavonol derivatives, rutin, hyperoside, xanthone derivatives, amentoflavone, biapigenin and ethereal oils.
- St. John's wort and St. John's wort extracts have already been employed for some considerable time in medicine and folk medicine as drugs for a wide variety of indications.
- the constituent hypericin has also recently come to be used in drugs as an active compound in isolated form (L. Roth, Hypericum, Hypericin, Ecomed medicinal plant monograph. Ecomed, Landsberg/Lech, 1990).
- the antidepressant activity which is comparable to that of the tricyclic antidepressants, of St. John's wort has been substantiated in a large number of placebo-controlled studies.
- St. John's wort oil is employed, in particular, for treating wounds and pain and in association with burns (L. Roth loc. cit.).
- hypericin was initially assumed to be the active compound in the St. John's wort oil.
- the formula of hypericin is depicted below:
- St. John's wort oil contains hyperforin (P. Maisenbacher et al., Planta Med. 58:351–354 (1992) and B. Hellwig, DAZ 137, 29, pages 35–36), whose formula is depicted below:
- hyperforin As an active compound, hyperforin has aroused interest as an antidepressant substance (Pharmacopsychiatry 1988, Vol. 31, Supplement 1, pages 1–60). In addition to this, hyperforin possesses antibacterial activity (A. I. Gurevich et al., L. Antibiotiki, 16:510–513 (1971).
- DE 195 47 317 discloses an antiviral medicament which is based on St. John's wort active compounds and which comprises 1–50% hypericin or pseudohypericin.
- EP-A-0 599 307 discloses a dry extract prepared from St. John's wort having an elevated content of hyperforin and also its use for producing drugs having psychovegetative and antidepressant activity.
- ointments which comprise a low concentration of Hypericum in addition to a variety of other medicinal herbs.
- these ointments are: “Unguentum Truw” for wound treatment and the homeopathic agent “Traumeel S”, which is an antiinflammatory agent, and “Atemaron N R30”, which is an analgesic/antirheumatic agent.
- Traumeel S which is an antiinflammatory agent
- Ambulon N R30 which is an analgesic/antirheumatic agent.
- hyperforin contains hyperforin.
- hyperforin because of the instability of hyperforin, it must be assumed that hyperforin is either not present, or only present in low quantities, if the extract is not prepared, stored and processed while being protected from light and oxidation. For example, it is not possible to detect any hyperforin in a commercially available Hypericum extract (Hyperforate).
- the known St. John's wort oil suffers from the disadvantage that, because of its fat content, it can only be used to a limited extent and is not suitable, for example, for treating eczemas. In addition to this, the oil only contains fat-soluble constituents of the St. John's wort and does not contain hypericin, for example.
- Cytostatic agents inhibit the growth, in particular, of rapidly growing cells as are found in tumours and leukaemias. They are therefore suitable for use as chemotherapeutic agents for the treatment of cancer. While a large number of chemotherapeutic agents are known, these compounds also suffer from disadvantages. In particular, treatment with known chemotherapeutic agents is accompanied by pronounced side-effects and most chemotherapeutic agents only exhibit satisfactory activity towards particular tumour cell lines.
- An object of the present invention is therefore to make available an additional chemotherapeutic agent for treating cancer diseases.
- Another object of the present invention is to make available a pharmaceutical formulation for the chemotherapeutic agent, which formulation does not suffer from the abovementioned disadvantages.
- the formulation it should be possible for the formulation to be adapted to a variety of skin conditions.
- the present invention consequently relates to the use of hyperforin for producing a drug for treating cancer diseases (primary tumors and metastases) and/or precancerous stages (cancer precursor stages).
- cancer diseases are understood, in particular, as meaning malignant tumours and also lymphomas and leukaemias.
- hyperforin is also particularly active against metastases, such as malignant melanoma (black skin cancer) metastases.
- Hyperforin has also proved to be effective against epithelial tumours such as epithelial skin cancer.
- This cancer is a slowly growing skin cancer which is readily accessible to topical treatment.
- Epithelial skin cancer is also termed spinalioma, squamous cell carcinoma or prickle cell cancer.
- hyperforin is also suitable for treating precancerous stages such as solar precancerous stages.
- hyperforin is suitable for treating mammary carcinomas (breast cancer).
- Hyperforin can be administered intravenously for treating systemic tumours and metastases.
- the lyophilized or dried active compound can, for example, be dissolved freshly in physiological saline solution and immediately injected or infused.
- the active compound can also be administered orally, for example in tablet form.
- hyperforin is also suitable for local administration, for example by means of injection or instillation (for example endoscopically as well) within or around the tumour.
- the active compound can, for example, be prepared for this purpose as described above for the intravenous administration.
- the active compound can also advantageously be applied by epicutaneous application, for example in the form of a cream, with this application form being particularly suitable, for example, for treating solar precancerous stages.
- the active compound can, for example, be dissolved in ethanol and worked into a greasy ointment base. This can take effect occlusively (under film) on the tumour, for example for a period of 24 hours.
- Particularly preferred ointments and creams are described in more detail below.
- the concentration of hyperforin at the site of action should be sufficiently high to ensure that an antiproliferative or apoptosis-inducing effect is elicited.
- the concentration which is required for this purpose can vary depending on the nature of the treated tumour and can be readily determined by the skilled person.
- a hyperforin concentration of 50 ⁇ g/ml in the administered solution is advantageous in the case of injection into a tumour while an active compound concentration of 100 ⁇ g/ ⁇ l is advantageous in connection with epicutaneous application.
- the active compound should be injected in quantities which are sufficient to ensure that plasma levels of at least 50 ⁇ g/ml are achieved. This corresponds to a hyperforin quantity of about 5 mg/kg of patient body weight.
- hyperforin can advantageously be administered in a pharmaceutical formulation which is in the form of a topical ointment or cream which comprises at least 15 ⁇ g of hyperforin/ml.
- the ointment or cream should contain a concentration of active compound which is as high as possible, preferably in the range of 0.02–20 mg of hyperforin/ml, more preferably in the range of 1–20 mg/ml and particularly preferably about 10 mg/ml (1% hyperforin).
- the ointment or cream according to the invention can additionally comprise hypericins as additional active compounds.
- the total concentration of the hypericins in the ointments or cream should be at least 15 ⁇ g/ml, preferably 20–150 ⁇ g/ml.
- hypericins are understood as meaning hypericin and its pharmaceutically active derivatives. These include, in particular, pseudohypericin, which differs from hypericin in that a methyl group is replaced with hydroxymethyl.
- the abovementioned active compounds can be introduced into the ointment or cream either as pure substances or in the form of a St. John's wort extract of defined concentration.
- the ointment or cream according to the invention preferably does not comprise any other plant extracts apart from the St. John's wort extract.
- a St. John's wort extract which contains at least 200 ⁇ g of hyperforin/ml and at least 200 ⁇ g of hypericins/ml is suitable for preparing the ointments or cream according to the invention.
- the extract employed preferably contains 200–100,000 ⁇ g/ml, in particular about 1000 ⁇ g of hyperforin/ml, and 200–1000 ⁇ g of hypericins/ml.
- the ointment or cream according to the invention should contain at least 5% by weight of the extract.
- an ointment according to the invention can, for example, contain about 15% by weight of the extract, and a cream according to the invention can contain about 10% by weight of the extract.
- the total extract which is standardized for hyperforin and hypericin should be an ethanolic extract or an extract to which ethanol has been added.
- the extracts can, for example, be commercially available total extracts (tinctures).
- the ethanol content is preferably between 20 and 60% v/v, preferably 40–50% v/v.
- aqueous extracts, CO 2 extracts or fresh plant extracts are also suitable provided they meet the requirements for the content of active compound.
- the St. John's wort extract which is used for the ointment or cream according to the invention is qualitatively and quantitatively analysed by means of high pressure liquid chromatography (HPLC) (P. Maisenbacher et al., Planta Med. 58:351–354 (1992)).
- HPLC high pressure liquid chromatography
- DAC Deutsche Arzneistoff-Codex [German Drug Codex]
- the ointment or cream according to the invention can comprise various pharmaceutically tolerated cream or ointment bases.
- these are white vaseline, viscous paraffin, wool wax, ascorbyl palmitate, glycerol monostearate 60, tocopherol (vitamin E), cetyl alcohol, medium-chain triglycerides, yellow wax, propylene glycol, Macrogol-1000-glycerol monostearate, citric acid, ascorbic acid and other preservatives and distilled water.
- a preferred ointment according to the invention comprises about 15% by weight of St. John's wort extract and white vaseline, viscous paraffin, wool wax and ascorbyl palmitate, in each case in suitable quantity.
- a preferred cream according to the invention comprises about 10% by weight of St. John's wort extract and also white vaseline, glycerol monostearate 60, cetyl alcohol, medium-chain triglycerides, yellow wax, propylene glycol, Marcogol-1000-glycerol monostearate, citric acid and water, in each case in suitable quantity.
- the present invention also relates to a process for preparing a topical ointment or cream, in which process hyperforin and, where appropriate, hypericins, or a St. John's wort extract which contains at least 200 ⁇ g of hyperforin/ml and at least 200 ⁇ g of hypericins/ml, is/are mixed with customary pharmaceutically tolerated adjuvants such that an ointment or cream having a minimum content of 15 ⁇ g of hyperforin/ml and, where appropriate, a minimum content of 15 ⁇ g of hypericins/ml, is obtained.
- this extract When a St. John's wort extract is used for preparing the ointment or cream according to the invention, this extract has, in order to protect the hyperforin from oxidation, to be stored in the dark and firmly sealed, and under a protective gas (e.g. argon), until it is processed.
- a protective gas e.g. argon
- the ointment or cream according to the invention is suitable, for example, for treating cancer diseases, precancerous stages, inflammatory skin diseases, geriatric skin and bacterial skin infections. Because of its fatty base, the ointment is particularly indicated in the case of dry, desquamative skin changes which are accompanied by pruritus or inflammations.
- the active compound content which is preferred for the ointment i.e. 15% by weight
- the active compound content which is preferred for the cream i.e. 10% by weight
- the cream i.e. 10% by weight
- the ointment according to the invention is consequently particularly suitable for treating chronic and also superinfected eczemas, exsiccation eczemas, hyperkeratotic hand and foot eczemas, subacute to chronic atopic dermatitis (neurodermatitis), lichen simplex, contact eczemas, prurigo simplex subacuta and other prurigo types, and psoriaris vulgaris of the plaque type, and also geriatric skin.
- the cream is particularly suitable for treating acute to subacute atopic dermatitis (neurodermatitis), acute to subacute contact eczemas, psoriasis and geriatric skin, and also for the after-treatment and relapse prophylaxis of all eczemas.
- the ointment and the cream can also be used in veterinary medicine, for example for treating inflammatory and infected skin diseases, such as mastitis (udder inflammation).
- hyperforin has a proliferation-inhibiting effect on human keratinocytes and lymphocytes.
- hypericin has a proliferation-inhibiting effect on keratinocytes (HaCaT) and T cells and can induce apoptasis in these cells. This effect is partially mediated by the formation of free oxygen radicals.
- the ointment or cream according to the invention has the advantage that its base can be adapted to various skin conditions.
- the cream is particularly suitable for treating acute and subacute dermatoses while the ointment is suitable for treating chronic dermatoses.
- both fat-soluble (hyperforin) and water-soluble (hypericin) active compounds from St. John's wort can be worked into an ointment or cream base. This makes it possible to achieve an effect which is superior to that of the known St. John's wort oil.
- the penetration of active compounds from cream and ointment bases is superior to that of active compounds from oils.
- novel ointment or cream for local topical use decisively enriches the spectrum of therapies for inflammatory skin diseases such as neurodermatitis.
- inflammatory skin diseases such as neurodermatitis.
- cortisone therapy the possibility exists of reducing cortisone therapy.
- FIG. 1 shows the antiproliferative effect of hyperforin on the tumour cell lines HT144 (human melanoma metastasis), A431 (human squamous cell carcinoma), Jurkat (human leukaemic lymphoma), 1F6 (human melanoma, primary tumour) and MT450 (rat mammary carcinoma) (Example 1).
- FIG. 2 shows the ability of hyperforin to induce apoptosis in the tumour cell lines HT144 (human melanoma metastasis), A431 (human squamous cell carcinoma), Jurkat (human leukaemic lymphoma), 1F6 (human melanoma, primary tumour) and MT450 (rat mammary carcinoma) (Example 2).
- FIG. 3 shows the apoptosis, due to the selective activation of caspases 9 and 3, which is induced by hyperforin (Example 5).
- FIG. 4 shows the ability of hyperforin to inhibit the tumour growth of mammary carcinoma cells in vivo in a similar manner to taxol (Example 6).
- FIG. 5 shows the proliferation-inhibiting effect on the cream according to the invention, as compared with that of St. John's wort oil, following use on healthy test subjects in vivo (Example 9).
- FIG. 6 shows the proliferation-inhibiting effect of hyperforin on HaCaT cells in vitro (Example 13).
- FIG. 7 shows the proliferation-inhibiting effect of hyperforin on PBMC in vitro (Example 14).
- FIG. 8 shows the proliferation-inhibiting effect of a cream which was standardized for hyperforin and of a Hypericum cream as compared with the immunosuppressive effect of a sun simulator irradiation (two times MED). Untreated skin was tested as the control (Example 15).
- FIG. 9 shows the proliferation-inhibiting effect of hyperforin in vitro (Example 16).
- tumour cells of the tumour cell lines HT144 human melanoma metastasis
- A431 human squamous cell carcinoma
- Jurkat human leukaemic lymphoma
- 1F6 human melanoma, primary tumour
- MT450 rat mammary carcinoma
- Hyperforin HWI-Analytik
- DMSO dimethyl methoxysulfoxide
- 1 ⁇ Curie of 3 H-thymidine was then added per well, and the incorporated radioactivity was measured in a scintillation counter (Canberra Packard) after 18 h.
- the radioactivity which is measured is proportional to the replication of the DNA in the cells.
- hyperforin induces apoptosis, i.e. what is termed programmed cell death, in tumour cells.
- apoptosis i.e. what is termed programmed cell death
- the induction of apoptosis in tumour cells is a characteristics feature of many cytostatic agents and provides supports for the view that hyperforin acts as such an agent.
- HT144 human melanoma metastasis
- A431 human squamous cell carcinoma
- Jurkat human leukaemic lymphoma
- 1F6 human melanoma, primary tumour
- MT450 rat mammary carcinoma tumour cells
- FIG. 2 depicts the extinction at 405 nm after subtracting the untreated control. It can be seen that hyperforin induces apoptosis, in a dose-dependent manner, in all the tumour cell lines.
- the following example proves that hyperforin and the known cytostatic agent taxol, used as a comparison substance, induce apoptotic DNA fragmentation.
- the DNA fragmentation was determined by means of DNA gel electrophoresis.
- Jurkat leukaemia
- caspases In order to demonstrate a possible mechanism of action for the induction of apoptosis by hyperforin, the activities of different caspases in tumour cell lines were investigated.
- the activation of caspases can be effected by a variety of signal transduction mechanisms and leads, by way of the activation of effector caspases (e.g. caspase 3) to induction of the programmed cell death.
- effector caspases e.g. caspase 3
- the activities of upstream caspase 9, downstream caspase 8 and effector caspase 3 were measured using a commercially available caspase kit (R&D Systems).
- MT450 cells were incubated with or without hyperforin (final concentration 50 ⁇ M) for 24 h at a concentration of 1 million cells/ml.
- the cells were centrifuged down and the supernatant was removed; the cells were then lysed with lysis buffer.
- the cell lysate was in each case incubated with a substrate which was specific for the caspase and the cleavage product, which was coupled to a dye, was detected photometrically in an ELISA reader.
- MT450 cells mammary carcinoma
- MT450 cells mammary carcinoma
- a treatment with the same concentrations of the cytostatic agent taxol was carried out for comparison.
- tumour volume was measured planimetrically 8 times, from the start of the tumour injections (day 0) until the conclusion of the treatment (day 30) and recorded as a growth curve (mean value +/ ⁇ standard deviation) in FIG. 4 . It is found that hyperforin significantly inhibits the growth of MT405 cells in vivo to the same extent as does taxol.
- a St. John's wort ointment was prepared in accordance with the following recipe (values in % by weight):
- the Vaseline, the viscous paraffin and the wool wax were heated to 60° C. in a water bath and mixed. The mixture was allowed to cool, while being stirred, with the ascorbyl palmitate being worked in during this period; the St. John's wort extract (total extract supplied by Caelo (hyperforin 240 ⁇ g/ml, hypericin 300 ⁇ g/ml)) was then worked in after the mixture had cooled down. The ointment which thus resulted contained 36 ⁇ g of hyperforin/ml and 45 ⁇ g of hypericin/ml.
- a St. John's wort cream was prepared in accordance with the following recipe (values in % by weight):
- the vaseline, the glycerol monostearate 60, the cetyl alcohol, the medium-chain triglycerides and the yellow was were heated to 60° C. in a water bath and mixed.
- the Macrogol-1000-glycerol monostearate, the propylene glycol, the water and the citric acid were heated separately to 60° C. in a water bath and then worked into the first mixture.
- the resulting mixture was stirred until it had cooled down and the St.
- John's wort extract total extract supplied by Caelo (hyperforin 240 ⁇ g/ml, hypericin 300 ⁇ g/ml)) was then worked in.
- the cream which thus resulted contained 24 ⁇ g of hyperforin/ml and 30 ⁇ g of hypericin/ml.
- MECLR mixed epidermal cell leukocyte reaction
- 50,000 EC were cocultured for 6 days (37° C., 5% CO 2 ) with 150,000 T cells (TC) in RPMI 1640 containing 10% foetal calf serum (FCS) containing 1% penicillin/streptomycin (all from Gibco) in 96-well flat-bottomed microtitre plates (Greiner). 1 ⁇ Curie of 3 H-thymidine (Amersham) was then added per well and the radioactivity which was incorporated was measured in a scintillation counter (Canberra Packard). The radioactivity which is measured is proportional to the replication of the DNA in the cells.
- FCS foetal calf serum
- penicillin/streptomycin all from Gibco
- This example demonstrates the proliferation-inhibiting effect of hyperforin on keratinocytes.
- HaCaT cells were cultured (37° C., 5% CO 2 ) in keratinocyte medium containing 10% foetal calf serum (FCS) containing 1% penicillin/streptomycin (all from Gibco). Subconfluent cultures were detached using EDTA-trypsin (Gibco), washed 3 ⁇ in PBS and then cultured for a further 24 h (until adherence) at a density of 20,000/well in 96-well flat-bottomed microtitre plates (Greiner).
- hyperforin HWI-Analytik
- HWI-Analytik hyperforin (HWI-Analytik) which had been freshly dissolved in DMSO was added for a period of 24 h.
- 1 ⁇ Curie of 3 H-thymidine (Amersham) was then added per well and the incorporated radioactivity was measured in a scintillation counter (Canberra Packard).
- the radioactivity which is measured is proportional to the replication of the DNA in the cells.
- the results for hyperforin concentrations of from 0 to 100 ⁇ g/ml are depicted in FIG. 6 , where cpm denotes counts per minute. It is found that proliferation is virtually completely inhibited at a hyperforin concentration of 100 ⁇ g/ml.
- PBMC peripheral blood mononuclear cells
- hyperforin cream containing a high proportion of hyperforin has an immunomodulatory effect in vivo. It was possible to demonstrate, by means of experiments using purified hyperforin, that this immunomodulatory effect is to be attributed to the hyperforin.
- the immunodulatory effect of the cream according to the invention was tested ex vivo in humans (in each case 4 test subjects). For this, skin samples which had been treated in different ways were removed and an investigation was carried out to determine whether the ability of epidermal Langerhans cells to present antigen is affected. In detail, this was investigated in an MECLR (mixed epidermal cell leukocyte reaction): In 4 test subjects in each case, round test areas of 2 cm in diameter on the flexor side of the lower arm were treated with Hypericum cream (containing 24 ⁇ g of hyperforin/ml and 30 ⁇ g of hyperin/ml), with hyperforin cream (24 ⁇ g/ml) or with sun simulator irradiation (144 J/cm 2 ).
- MECLR mixed epidermal cell leukocyte reaction
- FCS foetal calf serum
- FIG. 8 show that the hyperforin-containing St. John's wort cream and the hyperforin cream significantly inhibit proliferation to the same order of magnitude as does irradiation with the sun simulator.
- This example demonstrates the proliferation-inhibiting effect of hyperforin in vitro.
- use was made of pure hyperforin from HWI-Analytik (Rheinzabern). The purity of the hyperforin was >90%.
- the solvent DMSO was tested at the maximum concentration employed and did not exhibit any effect on the proliferation and vitality of the cells. Normal skin samples were removed from healthy test subjects; these samples were then incubated with hyperforin in vitro and an investigation was carried out to determine whether the ability of epidermal Langerhans cells to present antigen is affected.
- Example 14 This was investigated in an MECLR (mixed epidermal cell leukocyte reaction) as described in Example 14:
- MECLR mixed epidermal cell leukocyte reaction
- epidermal suction blisters were produced on the flexor side of the lower arm using a vacuum.
- the roof of the blister was dissected out under sterile conditions using a scalpel and a suspension of epidermal cells (EC) was prepared by treating with trypsin.
- a part of the EC or the TC was in each case incubated for 24 h with 24 ⁇ g of hyperforin/ml.
- the cells were washed and 50,000 EC were cocultured for 6 days (37° C., 5% CO 2 ) with 150,000 TC (T cells) in 1640 RPMI containing 10% foetal calf serum (FCS) containing 1% penicillin-streptomycin in 96-well flat-bottomed microtitre plates (Greiner). 1 ⁇ Curie of 3 H-thymidine (Amersham) was then added per well and, after 18 h, the incorporated radioactivity was measured in a scintillation counter (Canberra Packard). The radioactivity which is measured is proportional to the replication of the DNA in the cells.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19854446A DE19854446A1 (de) | 1998-11-25 | 1998-11-25 | Hyperforin-Salbe oder -Creme, deren Herstellung und Anwendung |
DE19913333A DE19913333C2 (de) | 1999-03-24 | 1999-03-24 | Hyperforin als Zytostatikum |
PCT/EP1999/009067 WO2000030660A2 (fr) | 1998-11-25 | 1999-11-24 | Hyperforine s'utilisant comme cytostatique et pommade ou creme a base d'hyperforine comme forme galenique d'application |
Publications (1)
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US7179495B1 true US7179495B1 (en) | 2007-02-20 |
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US09/856,694 Expired - Fee Related US7179495B1 (en) | 1998-11-25 | 1999-11-24 | Hyperforin as cytostatic agent and hyperforin ointment or cream as application form |
Country Status (10)
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US (1) | US7179495B1 (fr) |
EP (2) | EP1275382A3 (fr) |
AT (1) | ATE238045T1 (fr) |
AU (1) | AU1556800A (fr) |
CA (1) | CA2351947C (fr) |
DE (1) | DE59905230D1 (fr) |
DK (1) | DK1131063T3 (fr) |
ES (1) | ES2193765T3 (fr) |
PT (1) | PT1131063E (fr) |
WO (1) | WO2000030660A2 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019231499A1 (fr) * | 2018-05-31 | 2019-12-05 | Crititech, Inc. | Utilisation d'agents antinéoplasiques pour stimuler le système immunitaire pour le traitement du cancer |
US10507181B2 (en) | 2017-06-14 | 2019-12-17 | Crititech, Inc. | Methods for treating lung disorders |
US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
US10874660B2 (en) | 2016-04-04 | 2020-12-29 | CritlTech, Inc. | Methods for solid tumor treatment |
US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
JP2021532066A (ja) * | 2018-06-04 | 2021-11-25 | ケミストリーアールエックス.Chemistryrx. | 発毛を刺激するための局所的組成物 |
US11523983B2 (en) | 2017-06-09 | 2022-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10131641A1 (de) | 2000-12-22 | 2002-06-27 | Schwabe Willmar Gmbh & Co | Verbesserter und stabiler Extrakt aus Hypericum perforatum L., Verfahren zu seiner Herstellung und Verwendung als topisches Arzneimittel |
WO2003094945A1 (fr) * | 2002-05-07 | 2003-11-20 | Universitätsklinikum Freiburg | Utilisation d'hyperforine et de ses derives pour l'inhibition de l'angiogenese |
EP1522309A1 (fr) * | 2003-10-07 | 2005-04-13 | Dimitrios Skalkos | Extraits lipophiles d' Hypéricum perforatum pour le traitement du cancer |
DE102006058450A1 (de) * | 2006-12-12 | 2008-06-19 | Eberhard-Karls-Universität Tübingen | Zubereitungen zur Hemmung der Prostaglandin E2 Synthese |
DE102007013857A1 (de) | 2007-03-20 | 2008-09-25 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Neue Zusammensetzungen, insbesondere für die topische Behandlung von Hauterkrankungen |
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US4911925A (en) | 1989-04-17 | 1990-03-27 | Lima Shatkina | Vegetable extracts for skin treatment |
EP0424534A1 (fr) | 1989-04-28 | 1991-05-02 | DERYABIN, Alexandr Mikhailovich | Preparation pharmaceutique de traitement de la mastite chez l'animal et chez l'homme |
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RU2013093C1 (ru) * | 1985-06-26 | 1994-05-30 | Свистунова Раиса Павловна | Противовоспалительная и стимулирующая грануляцию кожной поверхности мазь |
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DE4239959A1 (de) * | 1992-11-27 | 1994-06-01 | Schwabe Willmar Gmbh & Co | Johanniskraut-Trockenextrakt, Verfahren zu seiner Herstellung und seine Verwendung |
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- 1999-11-24 CA CA002351947A patent/CA2351947C/fr not_active Expired - Fee Related
- 1999-11-24 DE DE59905230T patent/DE59905230D1/de not_active Expired - Lifetime
- 1999-11-24 AU AU15568/00A patent/AU1556800A/en not_active Abandoned
- 1999-11-24 DK DK99958118T patent/DK1131063T3/da active
- 1999-11-24 ES ES99958118T patent/ES2193765T3/es not_active Expired - Lifetime
- 1999-11-24 PT PT99958118T patent/PT1131063E/pt unknown
- 1999-11-24 US US09/856,694 patent/US7179495B1/en not_active Expired - Fee Related
- 1999-11-24 WO PCT/EP1999/009067 patent/WO2000030660A2/fr active IP Right Grant
- 1999-11-24 EP EP02022953A patent/EP1275382A3/fr not_active Withdrawn
- 1999-11-24 AT AT99958118T patent/ATE238045T1/de active
- 1999-11-24 EP EP99958118A patent/EP1131063B1/fr not_active Expired - Lifetime
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US10507181B2 (en) | 2017-06-14 | 2019-12-17 | Crititech, Inc. | Methods for treating lung disorders |
US11160754B2 (en) | 2017-06-14 | 2021-11-02 | Crititech, Inc. | Methods for treating lung disorders |
US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
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JP2021532066A (ja) * | 2018-06-04 | 2021-11-25 | ケミストリーアールエックス.Chemistryrx. | 発毛を刺激するための局所的組成物 |
Also Published As
Publication number | Publication date |
---|---|
AU1556800A (en) | 2000-06-13 |
ATE238045T1 (de) | 2003-05-15 |
CA2351947A1 (fr) | 2000-06-02 |
DE59905230D1 (de) | 2003-05-28 |
WO2000030660A3 (fr) | 2001-03-01 |
CA2351947C (fr) | 2008-10-21 |
EP1275382A3 (fr) | 2003-02-12 |
EP1131063A2 (fr) | 2001-09-12 |
EP1275382A2 (fr) | 2003-01-15 |
EP1131063B1 (fr) | 2003-04-23 |
ES2193765T3 (es) | 2003-11-01 |
PT1131063E (pt) | 2003-08-29 |
DK1131063T3 (da) | 2003-07-21 |
WO2000030660A2 (fr) | 2000-06-02 |
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